CRISPR/Cas9 as a tool to model and study cancer - insights and lessons learned

Presented at: CRISPR 2020
C.E. Credits: P.A.C.E. CE Florida CE
Speaker
  • Scientist, Octant
    Biography

      Originally from San Diego, CA, Grace moved to North Carolina for college and graduated from University of North Carolina at Greensboro in 2013 with a B.S. in Biology (biotechnology concentration) with chemistry and anthropology minors. In 2018, they completed their PhD in Kris Wood's lab at Duke University in the Molecular Cancer Biology program. Their work focused on utilizing functional genomics approaches to uncover novel vulnerabilities in cancers with intrinsic or acquired resistance to anti-cancer therapies. Following graduate school, Grace was a postdoctoral fellow at Stanford University in the Genetics Department where they worked closely with another postdoc to understand the genetic liabilities associated with 3D growth in cancer spheroid models. Currently, they are a scientist at an early stage drug development company that pairs multiplexed reporter assays and high-throughput chemistry to map chemical/biological interactions.


    Abstract

    Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers. However, the particular pathways that should be targeted to optimize therapeutic responses are unclear. Using CRISPR/Cas9, we systematically mapped the pathways whose inhibition cooperates with drugs targeting the KRAS effectors MEK, ERK, and PI3K. By performing 70 screens in models of KRAS mutant colorectal, lung, ovarian, and pancreas cancers, we uncovered universal and tissue-specific sensitizing combinations involving inhibitors of cell cycle, metabolism, growth signaling, chromatin regulation, and transcription. Furthermore, these screens revealed secondary genetic modifiers of sensitivity, yielding a SRC inhibitor based combination therapy for KRAS/PIK3CA double- mutant colorectal cancers (CRCs) with clinical potential. Surprisingly, acquired resistance to combinations of growth signaling pathway inhibitors develops rapidly following treatment, but by targeting signaling feedback or apoptotic priming, it is possible to construct three-drug combinations that greatly delay its emergence.

    Learning Objectives:

    1. Learn a scalable method to systematically define combination therapies in tissue culture models

    2. Identify challenges with two-body combination therapies in cancer

    3. Explain rational ways to design higher order combination therapies that forestall the emergence of resistance


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